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Heliyon May 2024Autism spectrum disorder (ASD) is a group of developmental diseases characterized by social dysfunction and repetitive stereotype behaviors. Besides genetic mutations,...
Autism spectrum disorder (ASD) is a group of developmental diseases characterized by social dysfunction and repetitive stereotype behaviors. Besides genetic mutations, environmental factors play important roles in the development of ASD. Valproic acid (VPA) is widely used for modeling environmental factor induced ASD in rodents. However, traditional VPA modeling is low-in-efficiency and the phenotypes often vary among different batches of experiments. To optimize this ASD-modeling method, we tested "two-hit" hypothesis by single or double exposure of VPA and poly:IC at the critical time points of embryonic and postnatal stage. The autistic-like behaviors of mice treated with two-hit schemes (embryonic VPA plus postnatal poly:IC, embryonic poly:IC plus postnatal VPA, embryonic VPA plus poly: IC, or postnatal VPA plus poly:IC) were compared with mice treated with traditional VPA protocol. The results showed that all single-hit and two-hit schemes produced core ASD phenotypes as VPA single treatment did. Only one group, namely, mice double-hit by VPA and poly:IC simultaneously at E12.5 showed severe impairment of social preference, social interaction and ultrasonic communication, as well as significant increase of grooming activity and anxiety-like behaviors, in comparation with mice treated with the traditional VPA protocol. These data demonstrated that embryonic two-hit of VPA and poly:IC is more efficient in producing ASD phenotypes in mice than the single-hit of VPA, indicating this two-hit scheme could be utilized for modeling environmental factors induced ASD.
PubMed: 38774072
DOI: 10.1016/j.heliyon.2024.e30617 -
Cureus Apr 2024Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing...
Fluvoxamine Ameliorates the Damage to the Neuro-Behavioral Status of Rats Caused by the Administration of Valproic Acid by Preventing Cognitive Memory Deficits and Decreased Hippocampal Cellular Proliferation.
Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing hippocampal cell division and proliferation. Valproic acid (VPA) is a commonly used antiepileptic drug and mood stabilizer that has negative effects on cognitive memory as it inhibits cellular division and proliferation in the hippocampus. This study assessed the protective effects of fluvoxamine treatment versus the memory impairment, decreased hippocampal cellular proliferation, and weight loss produced by VPA treatment. The cognitive memory of 40 male Sprague-Dawley rats was assessed by the novel object location (NOL) test. Immunostaining by Ki67 and glutathione peroxidase 1 (GPX-1) was performed to quantify the number of dividing cells in the subgranular zone (SGZ) of the dentate gyrus and to assess the antioxidant activity of different treatments, respectively. Results showed that the VPA group had fewer Ki67-positive cells than the control group (p < 0.001), indicating reduced hippocampal proliferation. In contrast, the VPA and fluvoxamine combination group showed increased proliferation (p < 0.001) compared to VPA alone. Notably, fluvoxamine treatment significantly differed in cell counts compared to other groups (p < 0.001). Fluvoxamine also attenuated the weight loss caused by VPA (p < 0.0001). Our data suggested that fluvoxamine therapy attenuated the VPA-induced decrease in SGZ cellular proliferation, memory, and weight in rats.
PubMed: 38770498
DOI: 10.7759/cureus.58578 -
Psychiatry and Clinical... Dec 2023This study's purpose is to determine the effects of current episode and the mood stabilizers on chorioretinal layer thicknesses of bipolar disorder (BD) patients using...
BACKGROUND
This study's purpose is to determine the effects of current episode and the mood stabilizers on chorioretinal layer thicknesses of bipolar disorder (BD) patients using spectral-domain optical coherence tomography (SD-OCT).
METHODS
Sixty-seven patients were diagnosed with BD I and using lithium (Li) or valproic acid (VPA), of whom 20 were manic, 24 were depressive, and 23 were in remission, and 49 healthy individuals were included in the study. Peripapillary retinal nerve fiber layer (RNFL), ganglion cell layer, and macular thicknesses of the participants were measured automatically using SD-OCT, and their choroid layer thicknesses were measured manually using the depth imaging mode of SD-OCT. Statistical analysis of the data was performed using Statistical Package for the Social Sciences version 23.0.
RESULTS
The patient group's mean age was 39.78 ± 11.78, and the control group's mean age was 42.06 ± 12.10. The mean disease duration was 13.22 ± 8.23 in the patient group, and 26 patients were using Li. While peripapillary RNFL thicknesses were lower in the patient group ( < .05), other layer measurements were similar between the groups. Moreover, the episodes experienced by BD patients did not affect chorioretinal SD-OCT measurements. The patients on VPA had significantly lower RNFL thicknesses compared to the control and the Li groups, and all chorioretinal measurements were similar between the Li and the control groups.
CONCLUSION
As a result of the study, it was established that neurodegenerative processes play a role in the pathophysiology of BD and the usage of Li is protective against the neurodegeneration of RNFL. Retinal changes measured with SD-OCT can be used for the diagnosis and prognosis of BD and for evaluating responses to mood stabilizers.
PubMed: 38765851
DOI: 10.5152/pcp.2023.23687 -
Pharmacogenomics and Personalized... 2024To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic...
PURPOSE
To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic variants and standardized blood levels of Valproic Acid (VPA) in schizophrenic patients, and evaluate the effects of age, gender, and Body Mass Index (BMI) on standardized VPA blood concentrations.
PATIENTS AND METHODS
Between February and December 2022, 192 Zhuang and Han schizophrenia patients treated with VPA were studied. Steady-state VPA concentrations were determined using homogeneous enzyme immunoassays, and *1, *2, and *3 loci via q-PCR. genotype distributions between Zhuang and Han groups in Nanning were compared using chi-square tests and contrasted with other ethnicities. Non-parametric tests analyzed VPA variations, identifying critical factors through multivariate stepwise regression.
RESULTS
The study identified five genotypes at the *2 and *3 loci, with the *3/*3 genotype absent in both cohorts. The distribution in Guangxi Zhuang and Han mirrors, yet diverges significantly from Hui and Kazakh groups. Among 192 subjects, VPA blood levels remained consistent across metabolic types and ages 18-60 but varied significantly by gender. Multivariate analysis revealed gender and BMI as significant factors, overshadowing genotype and age.
CONCLUSION
In Guangxi, genetic variants in Zhuang and Han schizophrenia patients demonstrate statistically indistinguishable allelic and metabolic distributions. Gender and BMI can influence standardized VPA blood concentrations in schizophrenia patients. However, in our study cohort, the genotype and age are not the primary determinants of standardized VPA blood levels.
PubMed: 38765788
DOI: 10.2147/PGPM.S457805 -
Scientific Reports May 2024Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic...
Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic acid (VPA), males typically display reduced sociability, while females are less affected. Although both males and females exhibit VPA effects on neuroinflammatory parameters, these effects are sex-specific. Notably, females exposed to VPA show increased microglia and astrocyte density during the juvenile period. We hypothesized that these distinct neuroinflammatory patterns contribute to the resilience of females to VPA. To investigate this hypothesis, we treated juvenile animals with intraperitoneal bacterial lipopolysaccharides (LPS), a treatment known to elicit brain neuroinflammation. We thus evaluated the impact of juvenile LPS-induced inflammation on adult sociability and neuroinflammation in female mice prenatally exposed to VPA. Our results demonstrate that VPA-LPS females exhibit social deficits in adulthood, overriding the resilience observed in VPA-saline littermates. Repetitive behavior and anxiety levels were not affected by either treatment. We also evaluated whether the effect on sociability was accompanied by heightened neuroinflammation in the cerebellum and hippocampus. Surprisingly, we observed reduced astrocyte and microglia density in the cerebellum of VPA-LPS animals. These findings shed light on the complex interactions between prenatal insults, juvenile inflammatory stimuli, and sex-specific vulnerability in ASD-related social deficits, providing insights into potential therapeutic interventions for ASD.
Topics: Animals; Female; Lipopolysaccharides; Prenatal Exposure Delayed Effects; Pregnancy; Mice; Valproic Acid; Social Behavior; Male; Autism Spectrum Disorder; Microglia; Disease Models, Animal; Behavior, Animal; Astrocytes; Mice, Inbred C57BL
PubMed: 38763939
DOI: 10.1038/s41598-024-62217-6 -
Neurotoxicology May 2024The valproic acid model has been shown to reproduce ASD-like behaviours observed in patients and is now widely validated for construct, face, and predictivity as ASD...
The valproic acid model has been shown to reproduce ASD-like behaviours observed in patients and is now widely validated for construct, face, and predictivity as ASD model in rat. The literature agrees on using a single exposition to 500 mg/kg of VPA at gestational day 12 to induce ASD phenotype with the intraperitoneal route being the most commonly used. However, some studies validated this model with repeated exposure by using oral route. The way of administration may be of great importance in the induction of the ASD phenotype and a comparison is greatly required. We compared two ASD models, one induced by a unique IP injection of 500 mg/kg of body weight at GD12 and the other one by repeated PO administration of 500 mg/kg of body weight/day between GD11 and GD13. The behavioural phenotypes of the offspring were assessed for the core signs of ASD (impaired social behaviour, stereotypical/repetitive behaviours, sensory/communication deficits) as well as anxiety as comorbidity, at developmental and juvenile stages in both sexes. The VPA IP model induced a more literature-compliant ASD phenotype than the PO one. These results confirmed that the mode of administration as well as the window of VPA exposure are key factors in the ASD-induction phenotype. Interestingly, the effects of VPA administration were similar at the developmental stage between both sexes and then tended to differ later in life.
PubMed: 38761921
DOI: 10.1016/j.neuro.2024.05.002 -
The Lancet. Neurology Jun 2024
Topics: Humans; Valproic Acid; Anticonvulsants; Epilepsy
PubMed: 38760090
DOI: 10.1016/S1474-4422(24)00141-8 -
The Lancet. Neurology Jun 2024
Topics: Humans; Valproic Acid; Anticonvulsants; Epilepsy
PubMed: 38760089
DOI: 10.1016/S1474-4422(24)00142-X -
Therapeutic Drug Monitoring May 2024Preliminary evidence shows that concomitant administration of valproic acid can reduce the exposure to dolutegravir with limited clinical impacts. Here, we describe a...
OBJECTIVE
Preliminary evidence shows that concomitant administration of valproic acid can reduce the exposure to dolutegravir with limited clinical impacts. Here, we describe a male living with HIV who experienced a drastic reduction in dolutegravir trough concentrations a few weeks after starting valproic acid treatment as identified by therapeutic drug monitoring. Concomitantly, pharmacists recommended a supplementation of magnesium to improve insomnia.
CASE REPORT
A 62-year-old man with HIV on antiretroviral therapy with dolutegravir and lamivudine recently added valproic acid to clonazepam and sertraline to treat severe sleep disturbances. An 84% reduction in dolutegravir trough concentrations was observed compared with the previous outpatient visit (418 versus 2714 ng/mL), with values close to the minimum effective drug concentration (300 ng/mL). Considering this, we strongly discourage the use of magnesium.
CONCLUSIONS
We are confident that our findings can contribute to a better understanding of the clinical problems that infectious disease physicians encounter in their daily management of people with HIV and how therapeutic drug monitoring may add value in this context. This case also highlights the importance of multidisciplinary services for the optimal management of polypharmacy in people with HIV.
PubMed: 38758630
DOI: 10.1097/FTD.0000000000001221 -
Cureus Apr 2024Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed. As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.
PubMed: 38756263
DOI: 10.7759/cureus.58416